Donor Human Milk Update: Evidence, Mechanisms and Priorities for
Research and Practice

Paula P. Meier, Director for Clinical Research and Lactation, Neonatal Intensive Care, Professor of Women, Children and Family Nursing, and Professor of Pediatrics, Rush University Medical Center, Chicago, IL, USA;

In the last decade, the use of pasteurized donor human milk (DHM) has become the
standard of care for very low birthweight (VLBW; <1500 g) infants throughout the
world when mothers’ own milk (MOM) is not available.1,2 DHM banks
have been established even in countries that use limited MOM feedings in the neonatal
intensive care unit (NICU).3,4 Little research informs this rapid practice
change. Multiple studies report that high-dose feedings of MOM during critical exposure
periods in the NICU hospitalization reduce the incidence, severity and risk of
potentially preventable morbidities including necrotizing enterocolitis (NEC); late
onset sepsis; chronic lung disease; retinopathy of prematurity; re-hospitalization after
NICU discharge and neurodevelopmental problems in infancy and childhood.5–11 However, this same constellation of outcomes has not been
attributed to DHM feedings.12
Furthermore, when compared with MOM and formula-fed infants, primarily DHM-fed infants
have demonstrated either slow weight gain or the need to “super-fortify”
DHM with exogenous bovine-based protein and other macronutrients,12–14. Separately, research and quality improvement projects have begun
to merge MOM and DHM into a common metric, human milk, despite the
marked differences in the composition, efficacy and associated costs of MOM and DHM. The
blurring of MOM and DHM outcomes has significant implications for the targeting of
resources that prioritize MOM feedings in the NICU. This paper reviews the evidence
about fundamental differences in MOM and DHM feedings for VLBW infants during the NICU
hospitalization and provides recommendations for practice and research.

MOM and DHM: Compositional and Bioactive Differences that Impact Outcome

Previous comparisons addressing the composition and bioactivity of MOM and
DHM have focused almost exclusively on the effects of pasteurization, with mixed
findings for some components.13,15,16 However, factors other than pasteurization impact DHM in
clinically significant ways including maturity of the mammary gland (preterm MOM
versus term DHM), stage of lactation for which DHM replaces MOM (e.g., mature DHM
replacing MOM colostrum and transitional milk), freeze-thaw cycles that are inherent
in the storage and processing of DHM.

Furthermore, the addition of bovine fortifier has never been studied
separately for DHM. For some MOM components, these factors are cumulative.
Lactoferrin provides an excellent example. Lactoferrin is a potent anti-infective,
anti-inflammatory, immunomodulatory and prebiotic substance in MOM that has been
linked to the reduction of NEC and sepsis.17–20
Lactoferrin concentrations are the highest in colostrum, and are higher in mothers
who deliver preterm versus term.21,22 Longitudinally, these
concentrations decrease by ≥ 50% between days 0–5 and days
11–30 of lactation, and continue to decline through two months of lactation
when they stabilize at approximately one-third of colostrum values (9g/L versus
2–3 g/L).21,22 Further reductions of 47–55%
occur with freezing.23,24 This means that lactoferrin concentrations
in DHM collected two months post-birth and frozen for three months may be as low as
1 g/L. Pasteurization further reduces baseline lactoferrin by up to
88%13 and
fortification with a bovine-based fortifier containing iron further reduces
remaining bioactivity.25 Thus,
even improved pasteurization processes cannot fully compensate for the sizeable
differences in some MOM and DHM components.

The most profound misfit between MOM and DHM occurs when preterm MOM is
replaced with DHM in the early post-birth period, a common clinical scenario due to
lack of MOM or concerns about maternal medications and health status. Pre-clinical
and human studies suggest that MOM produced as a function of mammary gland
immaturity and early stage of lactation is mirrored by specific biology in the
recipient infant during the early critical window post-birth. This potentiates
immunomodulatory and nutritional programming as well as selective organ growth,
including the immature brain.19,26–35 In particular the concentrations of high molecular weight
bioactive proteins (including growth factors, secretory IgA, lactoferrin,
interleukin 10, and soluble CD14) in preterm MOM are highest in colostrum but remain
elevated through the first month of lactation.36 The Table contrasts
MOM and DHM as a function of mammary maturity and stage of lactation for MOM.

Differences between MOM and DHM as a Function of Mammary Gland Maturity and Stage
of Lactation

MOM and DHM: Impact on Potentially Preventable Morbidities and Growth

DHM and Morbidities

There is empirical evidence for the efficacy of DHM in reducing the risk,
incidence and severity of NEC when DHM replaces formula.12,13,37–39 This consistent finding in
randomized and non-randomized studies is clinically and economically significant
regardless of the lack of impact on other acquired morbidities. However, most
DHM studies included some MOM feedings within a larger human
milk metric, with no information about the relative proportions of
MOM and DHM received before the onset of NEC. Because
bovine-based formulas may negatively impact the integrity of the immature gut
epithelial border in the early post-birth period as a function of increased
intestinal permeability,40 gut
epithelial cell toxicity,41
dysbiotic gut colonization42,43 and upregulation of
inflammatory responses;42 the
primary benefit of DHM may be the avoidance of formula.44 This knowledge has allowed clinicians to
introduce enteral feedings of DHM earlier post-birth instead of waiting for MOM
to become available. Thus, DHM may also contribute to reduction in NEC by
enabling earlier enteral feeding and reducing the inflammatory impact of
prolonged TPN.45

In contrast to MOM, studies about the use of DHM have not demonstrated a
reduction in either sepsis or chronic lung disease or a positive impact on
neurodevelopmental outcome in VLBW infants despite the reduction in
NEC.12–14,46 Numerous MOM components that are thought to contribute
to reduced sepsis, chronic lung disease and neurodevelopmental advantage are
reduced or absent in DHM, and include: myoinositol,28,47 antioxidants,48,49 lactadherin
and mucins,50 growth factors
such as insulin-like growth factor, transforming growth factor-β and
epidermal growth factor, soluble CD14 and adipokines.34,51–57

DHM and Slower Growth

Multiple studies reveal slower growth in DHM-fed versus MOM- and
formula-fed VLBW infants.7,12–14,38 To improve growth in DHM-fed infants, the most common
solution is DHM fortification that may involve the earlier introduction and
longer use of high concentrations of bovine protein.12–14,58 This practice
is based either on previous studies of MOM fortification or the need to
“super-fortify” DHM to achieve growth targets,13,14 rather than on separate long-term safety and efficacy
studies of DHM fortification. Non-protein factors may contribute to slower
growth in DHM-fed infants and should inform the development and testing of
alternative DHM enrichment strategies. For example, MOM adipokines including
leptin, adiponectin and ghrelin are linked to metabolic regulation in recipient
infants, and are thought to have a role in early nutritional
programming.52,59 These MOM hormones, for which
there are receptors in the fetal intestine, are present in preterm MOM, highly
concentrated in colostrum and transitional MOM, and reduced with
pasteurization.51–54,56 DHM may also decrease growth
due to the inconsistent delivery and utilization of MOM lipid.36,60 Freeze-thaw cycles alter the structure of the fat
globule membrane and its tightly regulated core and surface lipids,61 and multiple transfers of DHM
during storage and handling result in adherence of the non-homogenized lipid to
container surfaces.36,60 Furthermore, bile salt
stimulated lipase and lipoprotein lipase are completely inactivated and MOM
amylases and proteases are reduced with pasteurization,62 affecting macronutrient utilization even
though baseline values may be preserved with processing.

Combining MOM and DHM into the Same Human Milk Feeding Group for
Research and Quality Improvement

Most randomized studies comparing the effects of DHM and formula have
included infants receiving some MOM in both groups due to the inability to assign
feeding type ethically.7,14,38,63 However, other studies have used
the terminology, human milk-fed or breast
milk-fed, to include both MOM and DHM feedings without any information
detailing the relative proportions or the exposure periods for the two milks.
Human milk-fed has been used to describe characteristics of
study samples64 and as an outcome
variable in intervention studies.39,65 Recent systematic
reviews on the safety and efficacy of probiotics illustrate the limitations of using
a common human milk feeding grouping when differences in MOM and
DHM could impact outcome differently.64,66–68 Only one review discussed the potential
interaction between probiotics and type of feeding, but this comparison was between
MOM- and formula-fed infants, not MOM- and DHM-fed infants.68 In contrast to either formula or DHM, MOM
contains an array of mother-specific probiotic bacteria (milk microbiome) along with
highly complex and individual oligosaccharides that serve as prebiotics for these
specific probiotic bacteria.31,69 MOM-borne soluble CD14 and other
bioactive MOM components enable bacterial-enterocyte crosstalk in the
infant’s immature intestine.55 Pasteurization eradicates MOM probiotic bacteria and markedly
reduces MOM-borne soluble CD14, which declines over lactation.55,70
Thus, it is possible that DHM- and formula-fed infants would benefit from exogenous
probiotics more than exclusively MOM-fed infants,68 but available data do not inform this
important issue. Furthermore, from a safety and efficacy perspective, it is unknown
whether commercial probiotic strains compete with MOM probiotic bacteria for
substrate (MOM oligosaccharides), potentially displacing or altering the impact of
MOM probiotic bacteria on gut colonization.

Quality improvement initiatives focused on improving the use of human milk
in the NICU have increasingly combined MOM and DHM into a common indicator,
human milk feeding, even though this outcome was developed
originally for MOM feedings only.44,71 This limitation
is clinically significant because quality improvement initiatives about
human milk feeding are undertaken to reduce the prevalence of
specific morbidities for which MOM is known to be protective without similar
evidence for DHM. Thus, when high-dose human milk feedings
consisting mostly of DHM fail to reduce sepsis and are associated with slow growth,
these findings are generalized to MOM as well. Furthermore, the processes involved
in achieving high MOM feeding rates in the NICU are completely different from
acquiring DHM, and raise issues as to how resources should be prioritized to achieve
the quality initiative.

Impact of DHM Availability on Provision of MOM

One systematic review and one report of a large database of 22 California
NICUs have suggested that the introduction of DHM programs does not reduce rates of
provision of MOM for VLBW infants.39,72 However, the
measures used to evaluate the impact of DHM ranged from “any breastfeeding
at NICU discharge,” which was inconsistently defined among the studies, to
actual measures of MOM dose for specific exposure periods pre-and
post-implementation of a DHM program.39,72 Esquerra-Zwiers
et al reported a decrease in the cumulative proportion of MOM received by VLBW
infants at 14 and 28 days post-birth after the introduction of DHM into a NICU in
which 98% of these infants had received some MOM prior to DHM
availability.73 This
decrease was concentrated primarily among low-income mothers who, in previous
studies, changed the decision from formula to MOM following birth of a VLBW
infant.74 The study by
Kantorowska et al also revealed a racial difference in “any breastfeeding at
NICU discharge” following the introduction of DHM programs, with Black
mothers having lower odds of achieving this outcome.39

Acceptability of DHM by NICU Families and Staff

Several studies have examined the acceptability of DHM by NICU families and
staff in developing75–77 and developed78 countries. Concerns remain about the safety
and quality of DHM in developing countries, especially those in which the prevalence
of HIV is high.75,77 Brownell et al examined five-year trends in
non-consent for DHM in a large US urban medical center, reporting that non-White
race and increasing infant gestational age predicted refusal for DHM consent,
although total refusals decreased for each of the five years following
implementation of the DHM program.78 Other researchers have reported specific religious
considerations related to the use of DHM.79–81 Focusing
on the timing and framing of the DHM consent process,82 Esquerra-Zwiers found that mothers of VLBW
infants objected to being approached for DHM consent before their own attempts to
express MOM for their infants, and preferred a separate discussion about DHM that
was not bundled as a part of other procedure-related NICU consents.

The Economics of MOM and DHM and Prioritization of Resources

DHM reduces the costs associated with NEC when substituted for
formula,83 but is
significantly more costly than acquiring MOM,84 which reduces multiple other morbidities and their
associated costs in VLBW infants.6,8,36 These comparisons raise the question as to how investments in
human milk feeding should be targeted. Investing in DHM is
often easier than addressing barriers to the provision of MOM in the NICU, but most
lactation barriers in this population are modifiable when evidence-based practices
and resources are prioritized.85
The research literature is replete with strategies to acquire and feed MOM in the
NICU, including: assuring access to effective and efficient hospital-grade electric
pumps, double collection kits and customized breast shield sizing;86 implementing breast pump use
within 1 hour post-birth;87
avoiding exclusive hand expression in the early days post-birth;88 proactively monitoring pumped MOM volume
during the critical first two-weeks post-birth when breast-pump dependent mothers
are at risk for long-lasting MOM volume problems;86 integrating NICU-based breastfeeding peer
counselors as direct lactation care providers;85,89 and incorporating
tested lactation technologies such as milk analysis and test-weighing to objectively
manage growth on MOM feedings.36

Summary

Increasingly, the terminology human milk feeding is used to
include both MOM and DHM for VLBW infants, implying that the multiple beneficial
outcomes attributed only to MOM can be generalized to DHM. In particular, there is
lack of fit between preterm MOM and DHM during the early critical post-birth window
when nutritional and immunomodulatory programming and select organ growth via MOM
components are thought to occur. Although DHM has been associated with reductions in
NEC, MOM is more effective in the reduction of multiple morbidities and their costs
including NEC, and is less expensive to acquire than DHM. NICU care providers must
frame the argument for the superiority of MOM over DHM with families, peers and
hospital administrators in a manner that results in high doses and longer exposure
periods for MOM use in VLBW infants.

Acknowledgments

Funded by the National Institutes of Health (NR010009) and the Eunice Kennedy Shriver
National Institute of Child Health and Human Development (R03HD081412).

Abbreviations

DHM

Donor human milk

VLBW

Very low birthweight

MOM

Mother’s own milk

NICU

Neonatal Intensive Care Unit

Footnotes

The authors declare no conflicts of interest.

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Contributor Information

Paula P. Meier, Director for Clinical Research and Lactation, Neonatal Intensive Care, Professor of Women, Children and Family Nursing, and Professor of Pediatrics, Rush University Medical Center, Chicago, IL, USA.

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